Xiang Yun, Bernards Nicholas, Hoang Bryan, Zheng Jinzi, Matsuura Naomi
Department of Medical Imaging, University of Toronto, Ontario, Canada.
TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada.
Nanotheranostics. 2019 Mar 11;3(2):135-144. doi: 10.7150/ntno.29908. eCollection 2019.
Nanoscale perfluorocarbon (PFC) droplets have enormous potential as clinical theranostic agents. They are biocompatible and are currently used as contrast agents for a variety of medical imaging modalities, including ultrasound, computed tomography, photoacoustic and F-magnetic resonance imaging. PFC nanodroplets can also carry molecular and nanoparticulate drugs and be activated by ultrasound or light for targeted therapy. Recently, there has been renewed interest in using PFC nanodroplets for hypoxic tumor reoxygenation towards radiosensitization based on the high oxygen solubility of PFCs. Previous studies showed that tumor oxygenation using PFC agents only occurs in combination with enhanced oxygen breathing. However, recent studies suggest that PFC agents that accumulate in solid tumors can contribute to radiosensitization, presumably due to tumor reoxygenation without enhanced oxygen breathing. In this study, we quantify the impact of oxygenation due to PFC nanodroplet accumulation in tumors alone in comparison with other reoxygenation methodologies, in particular, carbogen breathing. Lipid-stabilized, PFC (i.e., perfluorooctyl bromide, CF(CF)Br, PFOB) nanoscale droplets were synthesized and evaluated in xenograft prostate (DU145) tumors in male mice. Biodistribution assessment of the nanodroplets was achieved using a fluorescent lipophilic indocarbocyanine dye label (i.e., DiI dye) on the lipid shell in combination with fluorescence imaging in mice (n≥3 per group). Hypoxia reduction in tumors was measured using PET imaging and a known hypoxia radiotracer, [F]FAZA (n≥ 3 per group). Lipid-stabilized nanoscale PFOB emulsions (mean diameter of ~250 nm), accumulated in the xenograft prostate tumors in mice 24 hours post-injection. PET imaging with [F]FAZA showed that the accumulation of the PFOB nanodroplets in the tumor tissues alone significantly reduced tumor hypoxia, without enhanced oxygen (i.e., carbogen) breathing. This reoxygenation effect was found to be comparable with carbogen breathing alone. Accumulation of nanoscale PFOB agents in solid tumors alone successfully reoxygenated hypoxic tumors to levels comparable with carbogen breathing alone, an established tumor oxygenation method. This study confirms that PFC agents can be used to reoxygenate hypoxic tumors in addition to their current applications as multifunctional theranostic agents.
纳米级全氟碳（PFC）液滴作为临床诊疗试剂具有巨大潜力。它们具有生物相容性，目前被用作多种医学成像模态的造影剂，包括超声、计算机断层扫描、光声成像和F磁共振成像。PFC纳米液滴还可携带分子和纳米颗粒药物，并通过超声或光激活以进行靶向治疗。最近，基于PFCs的高氧溶解度，人们对使用PFC纳米液滴进行缺氧肿瘤复氧以实现放射增敏重新产生了兴趣。先前的研究表明，使用PFC试剂进行肿瘤氧合仅在增强吸氧的情况下发生。然而，最近的研究表明，积聚在实体瘤中的PFC试剂可有助于放射增敏，推测是由于肿瘤复氧而无需增强吸氧。在本研究中，我们单独量化了PFC纳米液滴在肿瘤中积聚导致的氧合作用与其他复氧方法（特别是卡波金呼吸）相比的影响。合成了脂质稳定的PFC（即全氟辛基溴，CF(CF)Br，PFOB）纳米级液滴，并在雄性小鼠的异种移植前列腺（DU145）肿瘤中进行评估。使用脂质壳上的荧光亲脂性吲哚碳菁染料标记（即DiI染料）结合小鼠体内的荧光成像（每组n≥3）实现了纳米液滴的生物分布评估。使用PET成像和已知的缺氧放射性示踪剂[F]FAZA（每组n≥3）测量肿瘤中的缺氧减少情况。脂质稳定的纳米级PFOB乳液（平均直径约为250nm）在注射后24小时积聚在小鼠的异种移植前列腺肿瘤中。用[F]FAZA进行的PET成像显示，仅肿瘤组织中PFOB纳米液滴的积聚就显著降低了肿瘤缺氧，而无需增强氧气（即卡波金）呼吸。发现这种复氧效果与单独的卡波金呼吸相当。仅实体瘤中纳米级PFOB试剂的积聚就成功地将缺氧肿瘤复氧至与单独的卡波金呼吸相当的水平，卡波金呼吸是一种既定的肿瘤氧合方法。本研究证实，PFC试剂除了目前作为多功能诊疗试剂的应用外，还可用于使缺氧肿瘤复氧。
